1. Field of the Invention
This invention relates to a new process for producing azides from the corresponding benzylic alcohols or alpha hydroxy alkane esters with S.sub.N 2 inversion by the use of a phosphoryl azide and proton acceptor in a suitable solvent.
2. Brief Description of Disclosures in the Field
The synthesis of the orally active elastase inhibitor I below is described in J. Med. Chem. 1992, Vol. 35, p. 3745 by Shah, S. K. et al.: ##STR1## In the process of preparing closely related active derivatives, an enantiomerically pure amine 3 was required which on paper should be able to be produced through the azide 2. ##STR2##
An initial attempt to prepare the amine was made to activate the alcohol 1 by the known process of converting it to a sulfonate derivative and then displacing with an alkali azide. However, these efforts were abandoned because the activated alcohol was decomposing at temperatures far below that required for the displacement step (decomposition was observed at 0.degree. C.).
An examination of the literature provided few methods for alcohol to azide conversions which maintain optical activity with electron rich benzylic alcohols. Use of the Mitsunobu displacement with an azide nucleophile.sup.2 (note: The superscripts refer to literature references listed in the back of the specification) appeared to have the best precedent. Azide can be first introduced under Mitsunobu conditions using hydrazoic acid as the azide source.sup.3 and this method can be extended to chiral .alpha.-arylethylamines..sup.4 Alternatives to the use of hydrazoic acid include diphenyl-phosphoryl azide.sup.5 (DPPA), by Bose et al., and zinc azide/bis pyridine complex..sup.6
Applying the conditions of Bose et al..sup.4 to our substrate undesirably led to elimination product 5 and racemic azide 4, i.e., ##STR3##
In a modification of Bose's procedure the alcohol 1 and triphenylphosphine were added sequentially to a THF solution of diethylazodicarboxylate and DPPA at 0.degree. C. After 30 minutes the product was isolated using an aqueous workup. The azide 4 was isolated in 81% yield with only an optical purity of 82% ee. The reaction also undesirably produced 6-8% of the olefin 5. In addition, the azide was contaminated with 6 times its weight in Mitsunobu by-products so that an extensive chromatography was required, for purification. Undesirable loss of optical activity as well as olefin formation were attributed to highly reactive intermediates which can partition between ionization and displacement chemistry (S.sub.N 1 vs S.sub.N 2).
What is desired in the art is a process for converting an alcohol to an azide which undergoes a clean S.sub.N 2 inversion resulting in a high yield and enantiomeric purity of the azide product.